Scholarlink

Background and objectives <p>Autoantibodies (ABs) against intracellular proteins, including glutamate-decarboxylase 65 (anti-GAD65), are increasingly recognized in autoimmune and limbic encephalitis (AE/LE). Anti-GAD65 LE frequently progresses to severe temporal lobe epilepsy (TLE), neuropathologically characterized by hippocampal sclerosis (HS) and variable infiltration of cytotoxic T lymphocytes (CTLs). Recently, we have identified Drebrin (DBN) as a new intracellular target protein of ABs in index patients with suspected AE. Here, we aim to characterize key molecular and cellular signatures of hippocampal tissue from anti-GAD65- (GAD65-TLE) versus anti-DBN-positive TLE (DBN-TLE) patients correlated to clinical parameters.</p> Methods <p>We examined hippocampal neuropathology and performed exploratory single-nucleus RNA sequencing (snRNA-seq) of hippocampal tissue from DBN- and GAD65-TLE patients, integrated with key clinical data from a large patient cohort.</p> Results <p>Although the hippocampi of the two patient groups were neuropathologically virtually indistinguishable, exploratory snRNA-seq revealed distinct transcriptional programs. DBN-TLE patients (<i>n</i> = 2) showed transcriptional signatures enriched for forkhead box (Fox) transcription factor family, whereas GAD65-TLE patients (<i>n</i> = 2) displayed transcriptional signatures enriched for transcripts related to NF-κB- signaling. In a larger cohort, DBN-TLE patients (<i>n</i> = 22) showed significantly more favorable pharmacological responsiveness than GAD65-TLE patients (<i>n</i> = 35), who were largely pharmacoresistant. Notably, in a T cell-mediated mouse model for LE, similar inflammatory programs were dynamically regulated.</p> Conclusion <p>These findings provide a discovery-based transcriptomic signatures of rare autoimmune hippocampal tissue, revealing distinct immune-associated transcriptional states in anti-DBN- versus anti-GAD65-positive AE/TLE patients despite virtually indistinguishable hippocampal pathology in both groups and support further investigations of disease-specific therapeutic strategies.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Forkhead box versus NF-κB hippocampal snRNA-seq profiles distinguish anti-Drebrin- and anti-GAD65-positive encephalitis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月7日

查看全文
  • Karen M.J. van Loo,
  • Daniel S. Galvis-Montes,
  • Annika Breuer,
  • Juliane L. Berns,
  • Chiara A. Hummel,
  • Tobias Baumgartner,
  • Moritz Freyberg,
  • Katharina M. Mair,
  • Jan Bauer,
  • Theodor Rüber,
  • Ashley J. van Waardenberg,
  • Motaz Hamed,
  • Valeri Borger,
  • Hartmut Vatter,
  • Rainer Surges,
  • Susanne Schoch,
  • Albert J. Becker,
  • Julika Pitsch

摘要

Background and objectives

Autoantibodies (ABs) against intracellular proteins, including glutamate-decarboxylase 65 (anti-GAD65), are increasingly recognized in autoimmune and limbic encephalitis (AE/LE). Anti-GAD65 LE frequently progresses to severe temporal lobe epilepsy (TLE), neuropathologically characterized by hippocampal sclerosis (HS) and variable infiltration of cytotoxic T lymphocytes (CTLs). Recently, we have identified Drebrin (DBN) as a new intracellular target protein of ABs in index patients with suspected AE. Here, we aim to characterize key molecular and cellular signatures of hippocampal tissue from anti-GAD65- (GAD65-TLE) versus anti-DBN-positive TLE (DBN-TLE) patients correlated to clinical parameters.

Methods

We examined hippocampal neuropathology and performed exploratory single-nucleus RNA sequencing (snRNA-seq) of hippocampal tissue from DBN- and GAD65-TLE patients, integrated with key clinical data from a large patient cohort.

Results

Although the hippocampi of the two patient groups were neuropathologically virtually indistinguishable, exploratory snRNA-seq revealed distinct transcriptional programs. DBN-TLE patients (n = 2) showed transcriptional signatures enriched for forkhead box (Fox) transcription factor family, whereas GAD65-TLE patients (n = 2) displayed transcriptional signatures enriched for transcripts related to NF-κB- signaling. In a larger cohort, DBN-TLE patients (n = 22) showed significantly more favorable pharmacological responsiveness than GAD65-TLE patients (n = 35), who were largely pharmacoresistant. Notably, in a T cell-mediated mouse model for LE, similar inflammatory programs were dynamically regulated.

Conclusion

These findings provide a discovery-based transcriptomic signatures of rare autoimmune hippocampal tissue, revealing distinct immune-associated transcriptional states in anti-DBN- versus anti-GAD65-positive AE/TLE patients despite virtually indistinguishable hippocampal pathology in both groups and support further investigations of disease-specific therapeutic strategies.